Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach
<b>Background:</b> Both bromodomain and extra-terminal domain (BET) proteins and spleen tyrosine kinase (SYK) represent promising targets in diffuse large B-cell (DLBCL) and Burkitt’s lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZ...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/19/4691 |
| _version_ | 1797480267088134144 |
|---|---|
| author | Sina Sender Ahmad Wael Sultan Daniel Palmer Dirk Koczan Anett Sekora Julia Beck Ekkehard Schuetz Leila Taher Bertram Brenig Georg Fuellen Christian Junghanss Hugo Murua Escobar |
| author_facet | Sina Sender Ahmad Wael Sultan Daniel Palmer Dirk Koczan Anett Sekora Julia Beck Ekkehard Schuetz Leila Taher Bertram Brenig Georg Fuellen Christian Junghanss Hugo Murua Escobar |
| author_sort | Sina Sender |
| collection | DOAJ |
| description | <b>Background:</b> Both bromodomain and extra-terminal domain (BET) proteins and spleen tyrosine kinase (SYK) represent promising targets in diffuse large B-cell (DLBCL) and Burkitt’s lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. <b>Methods:</b> The effect of the single agents on cell proliferation and metabolic activity was evaluated in two DLBCL and two BL cell lines. Proliferation, metabolic activity, apoptosis, cell cycle and morphology were further investigated after a combined treatment of AZD or I-BET and Ento. RNAseq profiling of combined AZD+Ento treatment was performed in SU-DHL-4 cells. <b>Results:</b> Both BET inhibitors reduced cell proliferation and metabolic activity in a dose- and time-dependent manner. Combined BET and SYK inhibition enhanced the anti-proliferative effect and induced a G0/G1 cell cycle arrest. SU-DHL-4 demonstrated a pronounced modulation of gene expression by AZD, which was markedly increased by additional SYK inhibition. Functional enrichment analyses identified combination-specific GO terms related to DNA replication and cell division. Genes such as <i>ADGRA2</i>, <i>MYB</i>, <i>TNFRSF11A</i>, <i>S100A10</i>, <i>PLEKHH3</i>, <i>DHRS2</i> and <i>FOXP1-AS1</i> were identified as possible key regulators. <b>Conclusion:</b> Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature. |
| first_indexed | 2024-03-09T21:57:35Z |
| format | Article |
| id | doaj.art-56228acb4cf34b3f9b77e6af0badb670 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:57:35Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-56228acb4cf34b3f9b77e6af0badb6702023-11-23T19:55:01ZengMDPI AGCancers2072-66942022-09-011419469110.3390/cancers14194691Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro ApproachSina Sender0Ahmad Wael Sultan1Daniel Palmer2Dirk Koczan3Anett Sekora4Julia Beck5Ekkehard Schuetz6Leila Taher7Bertram Brenig8Georg Fuellen9Christian Junghanss10Hugo Murua Escobar11Hematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, GermanyHematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, GermanyInstitute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, GermanyInstitute for Immunology, Core Facility Genomics, Rostock University Medical Center, 18057 Rostock, GermanyHematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, GermanyChronix Biomedical GmbH, 37079 Goettingen, GermanyChronix Biomedical GmbH, 37079 Goettingen, GermanyInstitute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, GermanyInstitute of Veterinary Medicine, University of Goettingen, 37077 Goettingen, GermanyInstitute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, GermanyHematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, GermanyInstitute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany<b>Background:</b> Both bromodomain and extra-terminal domain (BET) proteins and spleen tyrosine kinase (SYK) represent promising targets in diffuse large B-cell (DLBCL) and Burkitt’s lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. <b>Methods:</b> The effect of the single agents on cell proliferation and metabolic activity was evaluated in two DLBCL and two BL cell lines. Proliferation, metabolic activity, apoptosis, cell cycle and morphology were further investigated after a combined treatment of AZD or I-BET and Ento. RNAseq profiling of combined AZD+Ento treatment was performed in SU-DHL-4 cells. <b>Results:</b> Both BET inhibitors reduced cell proliferation and metabolic activity in a dose- and time-dependent manner. Combined BET and SYK inhibition enhanced the anti-proliferative effect and induced a G0/G1 cell cycle arrest. SU-DHL-4 demonstrated a pronounced modulation of gene expression by AZD, which was markedly increased by additional SYK inhibition. Functional enrichment analyses identified combination-specific GO terms related to DNA replication and cell division. Genes such as <i>ADGRA2</i>, <i>MYB</i>, <i>TNFRSF11A</i>, <i>S100A10</i>, <i>PLEKHH3</i>, <i>DHRS2</i> and <i>FOXP1-AS1</i> were identified as possible key regulators. <b>Conclusion:</b> Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature.https://www.mdpi.com/2072-6694/14/19/4691BETI-BET151AZD5153entospletinibSYKgene expression |
| spellingShingle | Sina Sender Ahmad Wael Sultan Daniel Palmer Dirk Koczan Anett Sekora Julia Beck Ekkehard Schuetz Leila Taher Bertram Brenig Georg Fuellen Christian Junghanss Hugo Murua Escobar Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach Cancers BET I-BET151 AZD5153 entospletinib SYK gene expression |
| title | Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach |
| title_full | Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach |
| title_fullStr | Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach |
| title_full_unstemmed | Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach |
| title_short | Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach |
| title_sort | evaluation of the synergistic potential of simultaneous pan or isoform specific bet and syk inhibition in b cell lymphoma an in vitro approach |
| topic | BET I-BET151 AZD5153 entospletinib SYK gene expression |
| url | https://www.mdpi.com/2072-6694/14/19/4691 |
| work_keys_str_mv | AT sinasender evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT ahmadwaelsultan evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT danielpalmer evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT dirkkoczan evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT anettsekora evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT juliabeck evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT ekkehardschuetz evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT leilataher evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT bertrambrenig evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT georgfuellen evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT christianjunghanss evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach AT hugomuruaescobar evaluationofthesynergisticpotentialofsimultaneouspanorisoformspecificbetandsykinhibitioninbcelllymphomaaninvitroapproach |